Claudin peptidomimetics modulate tissue barriers for enhanced drug delivery

Sophie Dithmer, Christian Staat, Carolin Müller, Min Chi Ku, Andreas Pohlmann, Thoralf Niendorf, Nora Gehne, Petra Fallier-Becker, A. Kittel, Fruzsina R. Walter, S. Veszelka, Maria A. Deli, Rosel Blasig, Reiner F. Haseloff, Ingolf E. Blasig, Lars Winkler

Research output: Contribution to journalArticle

17 Citations (Scopus)


The blood-brain barrier (BBB) formed by themicrovascular endothelium limits cerebral drug delivery. The paraendothelial cleft is sealed by tight junctions (TJs) with a major contribution from claudin-5, which we selected as a target to modulate BBB permeability. For this purpose, drug-enhancer peptides were designed based on the first extracellular loop (ECL) of claudin-5 to allow transient BBB permeabilization. Peptidomimetics (C5C2 and derivatives, nanomolar affinity to claudin-5) size-selectively (≤40 kDa) and reversibly (12-48 h) increased the permeability of brain endothelial and claudin-5-transfected epithelial cell monolayers. Upon peptide uptake, the number of TJ strand particles diminished, claudin-5 was downregulated and redistributed fromcell-cell contacts to the cytosol, and the cell shape was altered. Cellular permeability of doxorubicin (cytostatic drug, 580 Da) was enhanced after peptide administration. Mouse studies (3.5 μmol/kg i.v.) confirmed that, for both C5C2 and a d-amino acid derivative, brain uptake of Gd-diethylene-triamine penta-acetic acid (547 Da) was enhanced within 4 h of treatment. On the basis of our functional data, circular dichroism measurements, molecular modeling, and docking experiments, we suggest an associationmodel between β-sheets flanked by α-helices, formed by claudin-5 ECLs, and the peptides. In conclusion, we identified claudin-5 peptidomimetics that improve drug delivery through endothelial and epithelial barriers expressing claudin-5.

Original languageEnglish
Pages (from-to)169-184
Number of pages16
JournalAnnals of the New York Academy of Sciences
Issue number1
Publication statusPublished - Jun 1 2017


  • Blood-brain barrier
  • Cell-cell contact
  • Claudin protein family
  • Peptide
  • Tight junction
  • Tissue barrier

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

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    Dithmer, S., Staat, C., Müller, C., Ku, M. C., Pohlmann, A., Niendorf, T., Gehne, N., Fallier-Becker, P., Kittel, A., Walter, F. R., Veszelka, S., Deli, M. A., Blasig, R., Haseloff, R. F., Blasig, I. E., & Winkler, L. (2017). Claudin peptidomimetics modulate tissue barriers for enhanced drug delivery. Annals of the New York Academy of Sciences, 1397(1), 169-184.